2-aminoxy-2&#39;-acyl-acetanilide

ABSTRACT

2-AMINOXY-2&#39;&#39;-ACYL-ACETANILIDES AND N-N2-AMINO-XPHENYLMETHYLENE) AMINOXYACETIC ACID LOWER ALKYL ESTERS (X=PHENYL, ALKYL AND CYCLOALKYL) AND SUBSTITUTED DERIVACTIVES THEREOF. THESE COMPOUNDS ARE INTERMEDIATES IN THE PREPARATION OF 4,1,5-BENZOXADIAZOCINES (A) AND KNOWN 1,4,BENZODIAZEPINS (B). A AND B ARE USEFUL AS SEDATIVES, MUSCLE RELAXANTS AND ANTICONVULSANT AGETS. A IS ALSO USEFUL AS INTERMEDIATES IN THE PREPARTION F B.

United States Patent Office 3,657,344 Z-AMINUXY-Z-ACYL-ACETANILIDEArthur Stempel, Teaneck, and Leo Henryk Sternbach, Upper Montclair,N.J., assignors to Hotfmann-La Roche Inc., Nutley, NJ.

N Drawing. Application Dec. 6, 1966, Ser. No. 600,347, now Patent No.3,420,817, dated Jan. 7, 1969, which is a continuation-in-part ofapplication Ser. No. 522,397, Jan. 24, 1966. Divided and thisapplication Oct. 17, 1968, Ser. No. 768,514

Int. Cl. C07c 103/42 U.S. Cl. 260-562 N 11 Claims ABSTRACT OF THEDISCLOSURE 2-Aminoxy-2'-acyl-acetanilides and N (2 amino X-phenylmethylene)aminoxyacetic acid lower alkyl esters (X=phenyl, alkyland cycloalkyl) and substituted derivatives thereof. These compounds areintermediates in the preparation of 4,1,5-benzoxadiazocines (A) andknown 1,4-benzorliazepines (B). A and B are useful as sedatives, musclerelaxants and anticonvulsant agents. A is also useful as intermediatesin the preparation of B.

RELATED APPLICATIONS This application is a division of co-pendingapplication Ser. No. 600,347, filed Dec. 6, 1966 now Pat. No. 3,420,-817 issued Jan. 7, 1969 in the names of Arthur Stempel and Leo HenrykSternbach, which in turn is a continuation-in-part of application Ser.No. 522,397, filed J an. 24, 1966 (now abandoned) also in the names ofArthur Stempel and Leo Henryk Sternbach. The benefit of the filing datesof these earlier filed applications is hereby claimed.

DETAILED DESCRIPTION The said 2-aminoxy-2'-acyl-acetanilides of theFormula V illustrated hereinafter and the said N-(Z-amino-X-phenylmethylene)-aminoxyacetic acid lower alkyl esters of the FormulaVIII illustrated hereinafter are intermediates in the preparation of4,l,S-benzoxadiazocin-Z-ones; which compounds are convertible into3-hydroxy-1,-4- benzodiazepin-Z-ones.

The said 3-hydroxy-benzodiazepines are of the formula wherein A isselected from the group consisting of lower alkyl and C -C cycloalkyl;R, R and R are selected from the group consisting of hydrogen, halogen,nitro, trifiuoromethyl and lower alkyl and R and R are each selectedfrom the group consisting of hydrogen and lower alkyl. l

A comprehensive survey of the various process aspects of the hereindisclosed invention may be had by reference to the followingdiagrammatical flow sheet wherein the symbols A, R, R R R and R have thesame significance as ascribed thereto hereinabove; X designates ahalogen atom, preferentially, selected from the group consisting ofchlorine, bromine and iodine, R is selected from the group consisting ofhydrogen and lower alkyl 3,657,344 Patented Apr. 18, 1972 Still morepreferred are those corn-pounds wherein R and R are both hydrogen, A isthe grouping and R is halogen, most advantageously, chlorine. In themost preferred embodiment, A is the grouping R, R and R are all hydrogenand R is halogen, preferentially, chlorine. When A is the grouping and Ris other than hydrogen, R is advantageously joined to the phenyl groupin the 2-position thereof and is, preferentially, fluorine.

XII

On reference to the flow sheet in which the process aspects of thepresent invention are illustrated graphically, one important aspectinvolves reacting a haloacetamidophenyl derivative, e.g. ahaloacetamidobenzophenone of the Formula II above, with a hydroxylaminederivative of the Formula III above which has its nitrogen functionprotected by a readily removable nitrogen protecting system. Byproceeding accordingly, there is obtained a novel Z-aminoxyacetanilideof the Formula IV above having its terminal nitrogen atom protected bythe system Z. The protecting system Z of the so-formed compound issubsequently removed whereby to obtain a novel 2- aminoxyacetanilide ofthe Formula V above.

Yet another important process variation involves reacting an anlinederivative of the Formula XI above with an amino-oxyacetic acidderivative which has its aminonitrogen function also protected by thereadily removable nitrogen protecting system Z to thereby obtain, in adifferent manner than that described in the preceding paragraph, thenovel Z-aminoxyacetanilides of the Formula Another important processaspect of the invention relates to a procedure for preparing novel4,1,5-benzoxadiazocin-Z-ones of the Formula VI above via the ringclosure of the said novel 2-aminoxy acetanilides of the Formula V above.

Still another important process variation relates to the reaction of ana-oxime of a 2-amino phenyl ketone of the Formula VII above with ahaloacetic acid or an ester thereof to thereby prepare a novel imine(Schitfs Base) of the Formula VIII above and ring closing the sameto thecorresponding 4,1,5-benzoxadiazocin-2-one of the Formula VI.

Still another important embodiment of the present invention relates to aprocess for converting the said 4,1,5- benzoxadiazocin-2-ones of theFormula VI above into a 1,4-benzodiazepin-2-one bearing a hydroxy groupin position-3 of the Formula I above.

As is indicated above, compounds of the Formula IV, V, VI and VIII arenovel and are useful in view of their capability of being converted intotherapeutically desirable compounds. Thus, such compounds constitute apart of the present invention.

Again, referring to the diagrammatical flow sheet illustratedgraphically hereinabove and considering in greater detail the varioussteps and stages of the processes of the invention disclosed therein,the stage II- IV comprises the conversion of a 2-haloacetamido phenylketone of the Formula H above, e.g. a 2-haloacetamidobenzophenone, intoa Z-aminoxyacetanilide of the Formula IV (e.g. a2'-benzoyl-Z-aminoxyacetanilide) having the terminal amino functionthereof protected by a suitable protecting system via the reaction ofthe former with a hydroxylamine derivative of the Formula III abovewhich has the nitrogen function thereof protected by the said protectingsystem Z. Said protecting system Z is comprised of a group or groupswhich are readily removable by conventional procedures, well documentedin the literature. All that is required of the protecting system Z inorder to render it suitable for the purposes of the present invention isthat it be an operable protecting system for the nitrogen function of acompound of the Formula III above, that is, that it protects against theformation of unwanted side products insofar as the present invention isconcerned, which would result if a compound of the Formula III abovewere to join to the compound of the Formula II above through the 2-aminonitrogen function of the latter. Systems for which the character Z isassigned and which will function efficaciously for the purposes of thepresent invention are those which consist of the phthaloyl group, alower alkylidene group, e.g. isopropylidene, a benzal group or onecarbobenzoxy group and one hydrogen group. Representative ofhydroxylamine derivatives bearing a protecting group falling within thescope of the genus encompassed by Formula III above are N-hydroxyphthalimide, lower alkylidene oximes, such as acetone oxime,N-carbobenzoxy hydroxylamine, benzaldoxime and the like. It is, ofcourse, to be understood that the compounds expressly named herein whichare encompassed by the genus illustrated in Formula III above are onlyexemplary of many the artisan would recognize are included Within thepurview of the present invention. Thus, from the above, it should beevident that the character of the system Z as illustrated in thehereinabove formulae is not critical and that for the system Z to beusable for the purposes of the present invention, it need only protectthe nitrogen function of a compound of Formula III above fromparticipating in the above-described first-stage reaction step andcontain leaving groups which are readily removable by well establishedtechniques, whereby to render the terminal nitrogen atom capable ofparticipating in subsequent reaction steps.

Advantageously, the first stage (II- IV) is effected in the presence ofan inert organic solvent such as an ether, e.g. tetrahydrofuran and thelike. To insure good yields of the compounds of the Formula IV above,there is preferentially provided in the reaction zone, a tertiaryorganic base which functions as an acid acceptor to accept thehydrohalic acid formed. Suitable organic bases are tertiary amines suchas tri-lower alkylamines, e.g. triethylamine, dimethylaniline,diethylaniline and the like. While temperature is not a critical aspectof this stage, elevated temperatures are preferred, e.g. at about thereflux temperature of the reaction medium. Thus, the reaction isconveniently effected by heating the reactants together, while agitatingwell, preferably in the presence of tertiary organic bases as acidacceptor.

The stage IV V, i.e. the stage in which the removal of the protectingsystem is effected, as is noted above, is conducted utilizingconventional procedures well established in the art. For example, if Zin Formula IV above consists of a phthaloyl group as the protectivegroup, the system and its function is removed by treating such compoundswith hydrazine hydrate, whereby to prepare the corresponding compound ofthe Formula V above. If the system Z in a compound of the Formula IVabove consists of a lower alkylidene group, e.g. an isopropylidenegroup, said group being joined to the terminal nitrogen atom of thecompound of the Formula IV above, the conversion of the last-mentionedcompound is effected utilizing a dilute mineral acid, e.g. dilutehydrochloric acid. If Z in the Formula IV above consists of theremovable group, benzal, the conversion of a so-substituted compound ofthe Formula IV above to the corresponding compound of the Formula Vabove can be similarly effected utilizing dilute mineral acids. If thesystem Z consists of carbobenzoxy as the removable group and hydrogen,then removal of the system and its function is effected utilizing ahydrogen bromide-acetic acid mixture. Preferably, the conversion of acompound of the Formula IV above to the corresponding compound of theFormula V above is effected under mild conditions, for example, at roomtemperature.

The (V VI) is a particularly novel aspect of the present invention sinceit results in the unexpected ring closure of a compound of the Formula Vabove to a novel compound of the Formula VI above. Preferentially, thisprocess step is conducted in the presence of an organic base such aspyridine, picoline, quinoline and the like or a salt thereof or mixturesof the salt and free base. Alternatively, any suitable inert organicsolvent such as a lower alkanol, an ether such as tetrahydrofuran,dimethylformamide and the like, can serve as the reaction medi um. Whilean organic base is indicated above as being preferentially provided inthe reaction medium, it is, of course, to be understood that the same isnot necessary to a successful performance of this process step and thering closure can be effected, although with diminished yields, in aninert organic solvent per se and/or on long standing at room temperatureand/or at elevated temperatures. Temperature and pressure are notcritical aspects of this process step and thus the reaction can beeffected at room temperature or above or below room temperature andatmospheric pressure. However, elevated temperatures, i.e. at about thereflux temperature of the reaction medium, are preferred.

The last stage of the process illustrated graphically above involvestreating a compound of the Formula VI above with a base to unexpectedlyobtain rearrangement to the desired 3-hydr0xy benzodiazepin-Z-ones ofthe Formula I above. Any suitable base which is capable of effecting thedesired end can be suitably employed in this process stage.Representative of such are alkali metal hydroxides, e.g. sodiumhydroxide; alkaline earth metal hydroxides; alkylates, e.g. alkali metalalkylates, such as sodium methoxide, sodium ethoxide and the like.Advantageously, the last stage is conducted in the presence of an inertorganic solvent such as dioxane, tetrahydrofuran, dimethylformamide,lower alkanols such as ethanol and methanol and the like and at roomtemperature and atmospheric pressure, although if the reaction isconducted above or below room temperature, the desired end can also beeffected.

Another stage in the process illustrated diagrammatically above involvesthe step of reacting a compound of the Formula XI with a compound of theFormula XII whereby to obtain a corresponding compound of the FormulaIV. This stage (XI-l-XII IV) comprises the conversion of the Z-carbonylgroup containing aniline derivatives of the Formula XI, e.g. a2-amino-benzophenone, a (2-methyl amino phenyl)lower alkyl ketone or a(Z-amino phenyl)-C C cycloalkyl ketone, into the 2-aminoxy acetic acidaniline of the Formula IV above which has the amino function thereofprotected by the protecting system Z. The conversion is effected byreacting the compound of the Formula XI with an aminoxy aceticderivative of the Formula XII which has the nitrogen function thereofprotected by the above-identified protecting system Z. Representative ofaminoxyacetie acid derivatives bearing a protecting group falling withinthe scope of the genus encompossed by Formula XII above arecarbobenzoxyaminoxyacetic acid, phthalimidoxyacetic acid, loweralkylideneaminoxy acetic acid, benzaldaminooxyacetic acid and the like.It is, to be understood that the compounds expressly named herein whichare encompassed by the genus illustrated in Formula XII above are onlyexemplary of the many the artisan would readily recognize are suitablefor the purposes of the present invention and hence, are included withinthe purview thereof.

Advantageously, the conversion of the compound of the Formula XI aboveto the corresponding compound of the Formula IV above is effected in thepresence of an inert organic solvent which may be a chlorinatedhydrocarbon such as methylene chloride, ethers such as tetrahydrofuran,an aromatic hydrocarbon such as benzene and toluene and the like. In apreferred aspect, when converting the compounds of the Formula XI aboveto the corresponding compounds of the Formula IV above, a condensingagent is present. Among the many condensing agents suitable for thepurposes of the present invention there may be includedN,N'-dicyclohexylcarbodiimide, thionyl chloride, polyphosphoric acid andthe like. Most preferred is N,N-dicyclohexylcarbodiimide. Temperatureand pressure are not critical aspects of this process variation.Accordingly, the process can be carried out at room temperature and atelevated temperatures. However, in a preferential aspect, the process iscarried out below room temperature, most preferably, from a temperatureof 0 C. to about C.

Another stage in the process illustrated diagrammatically above involvesthe route from VII VI*II- VI. When converting the compound of theFormula VII above (a compound which contains an oxirne group, syn withrespect to the amino substituted phenyl group),

to the corresponding compound of the Formula VIII above, with ahaloacetic acid or an ester thereof, there is present as the reactionmedium, an inert organic solvent which may be a lower alkanol such asmethanol, ethanol and the like, an ether such as dioxane,tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide and the like.Preferably, the reaction medium in which the conversion is effected ismade basic by the addition thereto of a basic material, preferably, amaterial which is strongly basic, such as a lower alkali metalhydroxide, e.g. sodium hydroxide, a lower alkali metal alkoxide, e.g.sodium methoxide and the like. While temperature and pressure are notcritical aspects of this process variation, it is preferred to operateat elevated temperatures, most preferably, at about the refluxtemperature of the reaction medium.

The conversion of the compounds of the Formula VIII above to thecorresponding compounds of the Formula VI above is suitably effected inthe presence of a cyclization agent and an inert organic solvent mediumsuch as tetrahydrofuran and the like. Any suitable cyclization agentwhich is capable of achieving the desired end can be eflicaciouslyemployed in this process variation. Illustrative of such areN,N-dicyclohexyl-carbodiimide, ptoluene sulphonic acid, thionylchloride, polyphosphoric acid and the like. In a preferred embodiment,in this ring closing step when R is H, the cyclization agent utilized isN,N'-dicyclohexylcarbodiimide. In this process step, temperature andpressure are not critical. However, when R is hydrogen, it is preferredto operate below room temperature, preferentially in a range from about0 C. to about 25 C. When R is lower alkyl, elevated temperatures arepreferred, e.g. at about the reflux temperature of the reaction medium.

Compounds of Formula VI above are useful not only as intermediates inthe preparation of compounds of known therapeutic value but areadditionally useful as anticonvulsant, muscle relaxant and sedativeagents. Particularly useful for such purposes are compounds of theFormula VI above wherein R is lower alkyl, e.g. methyl and A is thegrouping wherein R is as above. The compounds of Formula VI above can beadministered, parenterally or enterally, with the dosage regimenadjusted to fit the exigencies of a particular pharmacologicalsituation. They can be compounded in conventional pharmaceutical dosageforms to provide capsules, tablets, elixirs, suppositories, suspensions,emulsions and the like.

Compounds of Formula VI above wherein R is lower alkyl can besynthesized from compounds of Formula VI above wherein R is hydrogen byalkylating such compounds. The alkylation can be efficaciously effectedby treating compounds corresponding to Formula VI above wherein R ishydrogen with, for example, an alkali metal hydride, e.g. sodium hydrideor an alkali metal alcoholate such as sodium methoxide in the presenceof an inert organic solvent such as toluene, dimethylformamide and thelike to thereby form the sodio derivative of such compounds and thenreacting the sodio derivative with an alkylating agent, e.g. a di-loweralkyl sulfate or a lower alkyl halide. Suitable dialkyl sulfates may berepresented by dimethyl sulfate. Similarly, suitable alkyl halides maybe represented by methyl iodide.

The term lower alkyl as utilized hereinabove is intended to representstraight or branched chain hydrocarbon groups such as methyl, ethyl,propyl, isobutyl and the like. The term halogen as employed hereindesignates all four forms thereof, chlorine, fluorine, bromine andiodine, unless otherwise specified. The expression 7 C C cycloalkylconnotes a cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl andcycloheptyl group.

The foregoing is a description of new and valuable processes for thepreparation of pharmaceutically useful3-hydroxy-1,4-benzodiazepin-2-ones and novel intermediates useful intheir preparation. It will be readily apparent to one skilled in the artthat variations of these procedures are possible.

The following examples are illustrative but not limitative of theprocess for preparing the aforesaid 3-hydroxybenzodiazepin-2-ones, thenovel intermediates useful in the preparation thereof and novelbenzoxadiazocines which are additionally useful for pharmaceuticalpurposes. All temperatures are stated in degrees centigrade.

EXAMPLE 1 A mixture of g. (28 mmoles) of 2'-benzoyl-2-bromo-4'-chloroacetanilide and 4.6 g. (28 mmoles) ofN-hydroxy-phthalimide in 60 ml. of tetrahydrofuran containing 8.6 ml. oftriethylamine was stirred and heated to reflux for a period of 75minutes. The resultant mixture was then filtered. On addition of hexaneto the filtrate, crystallization occurred. Filtration separated 2-benzoyl-4'-chloro-2-phthalimidoxyacetanilide, melting at 179-181.5.Recrystallization from ethyl acetate gave the product melting at183-184.

EXAMPLE 2 A mixture of 21.6 g. (59 mmoles) of 2'-benzoyl-2-bromo-4'-nitroacetanilide and 9.6 g. (59 mrnoles) of N-hydroxyphthalimide in 130 ml. of tetrahydrofuran and 18.1 ml. oftriethylamine was stirred and heated to reflux for 75 minutes. It wasthen filtered. On addition of hexane to the tetrahydrofuran filtrate,2-benzoyl-4'-nitro- 2-phthalimidoxyacetanilide melting at l83.5185crystallized. Recrystallization from ethyl acetate gave cream coloredneedles melting at 203-204".

EXAMPLE 3 A mixture of 24.2 g. (63 mmoles) of 2'-benzoyl-2-bromo-4-trifiuoromethylacetanilide and 10.3 g. (63 mmoles) ofN-hydroxyphthalimide in 135 ml. of tetrahydrofuran and 19.3 ml. oftriethylamine was stirred and heated to reflux for 75 minutes. Theresultant mixture was then filtered. Upon addition of hexane to thefiltrate, crystallization occurred. Filtration separated crude 2'-benzoyl-4'-trifluoromethyl 2 phthalimidoxyacetanilide melting at184-189". Recrystallization from ethylacetate gave the product meltingat 191193.

EXAMPLE 4 Using the procedure described in Example 3,2-benzoyl-2-phthalimidoxyacetanilde melting at 174176 was prepared byreacting 2'-benzoyl-2-bromoacetanilide with N-hydroxyphthalimide.

EXAMPLE 5 To a solution of 6.8 g. (16 mmoles) of 2'-benzoyl-4'-chloro-2-phthalimidoxyacetanilide in a mixture of 80 ml. of chloroformand 80 ml. of ethanol, 1.8 g. (37 mmoles) of hydrazine hydrate and 1.8ml. of water were added. After standing for 18 hours at roomtemperature, the mixture was filtered. The filtrate was concentrated toa small volume under reduced pressure and the residue was thenpartitioned between dilute ammonia water and ether. The ether layer wasseparated and extracted with a 5% solution of hydrochloric acid. Theacidic extracts were combined, made slightly basic with dilute sodiumhydroxide and extracted with ether. The organic layer was dried oversodium sulfate and concentrated to dryness. The residue crystallized onstanding. Recrystallization from a mixture of benzene and hexane gaveZ-aminoxy 2'-benzoyl-4-chloroacetanilide.

EXAMPLE 6 As in Example 5, 2-aminoxy-2'-benzo'yl-4'-nitroacetan- 8 ilidewas prepared from 2'-benzoyl-4-nitro-2-phthalimidoxyacetanilide. Itmelted at 141143 after crystallization from a mixture of benzene andhexane.

EXAMPLE 7 As in Example 5, 2-aminoxy-2-benzoyl-4'-trifiuor0-methylacetanilide was prepared from2'-benzoyl-4-trifiu0romethyl-Z-phthalimidoxyacetanilide. It crystallizedfrom hexane as colorless plates melting at 798l EXAMPLE 8 As in Example5, 2-aminoxy-2'-benz0ylacetanilide was prepared from2'-benzoyl-Z-phthalimidoxyacetanilde.

EXAMPLE 9 A solution of 5 g. 16 mmoles) of2aminoxy-2-benzoyl-4'-chloroacetanilide in ml. of pyridine was carefullyadded over a period of 1 hour to a stirred, refiuxing solution of 5 g.of pyridine hydrochloride in 600 ml. of pyridine. Upon completion, therefluxing was continued for an additional 6 hours. Solvent was thendistilled off under reduced pressure and the residue was partitionedbetween methylene chloride and water. The organic layer was washedsuccessively with dilute hydrochloric acid, 5% sodium bicarbonatesolution and water. After drying over sodium sulfate, the solvent wasremoved by distillation and the residue crystallized from ethyl acetate.The filtrate was distilled to remove ethyl acetate and the residue wascrystallized from benzene to give 8-ch1or0-1,3-dihydro-6-phenyl-2H-4,1,S-benzoxadiazocin-Z-one melting at 197198.5.Further crystallization did not alter the melting point.

EXAMPLE 10 As in Example 9,1,3-dihydro-6-phenyl-2H-4,1,S-benzoxidiazocin-Z-one was prepared fromthe 2-aminoxy-2'- benzoylacetanilide synthesized in Example 8 and wasfound to have a melting point of 236-238 after crystallization frombenzene.

EXAMPLE 1 1 As in Example 9, 1,3-dihydro-8-nitro-6-phenyl-2H-4,1,S-benzoxadiazocin-Z-one was prepared from2-aminoxy-2-benzoyl-4'-nitroacetauilide. The so-prepared product had amelting point of 253255 after crystallization from methylene chlorideand hexane.

EXAMPLE 12 As in Example 9, 1,3-dihydro-8'trifiuoromethyl-6-phenyl-2H-4,1,5-benzoxadiazocin 2 one was prepared from2-aminoxy-2-benzoyl-4-trifiu0romethyl acetanilide. The so-preparedproduct had a melting point of 212214 after crystallization frommethylene chloride and hexane.

EXAMPLE 13 A solution of 1 g. (3.5 mmoles) of8-chloro-1,3-dihydro-6-phenyl-2H-4,1,5 benzoxadiazocin-2-one in 100 ml.of dioxane containing 3.5 ml. of 2 N sodium hydroxide (7 mmoles) wasstirred for 20 hours. A solid formed after about 3 hours of stirring.The solid was separated by filtration and gave the gave the sodium saltof 7-chloro 1,3 dihydro 3 hydroxy 5 phenyl-2H- 1,4-benzodiazepin-2-onemelting at -205 A solution of this product in 100 ml. of ethanol and 45ml. of water (pH 12.2) was acidified to pH 1.7 by the addition of 3 Nhydrochloric acid. One concentration of the acidic solution underreduced pressure,7-chloro-1,3-dihydro-3-hydroxy-S-phenyl-ZH-1,4-benzodiazepin-2-onecrystallized.

EXAMPLE 14 To a solution of 1.0 g. (3.5 mmoles) of 8-chloro-1,3- dihydro6 phenyl 2H 4,1,5 benzoxadiazocin-Z-one in 50 ml. of methanol, there wasadded 2.5 ml. of 2.79 N sodium methoxide in methanol (7 mmoles). Theresultant reaction medium was stirred for min. The solid that separatedwas removed by filtration to give the sodium salt of7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4- benzodiazepin-Z-one,M.P. 196-210" dec. The last-mentioned salt was dissolved in 70 ml. of50% aqueous ethanol and acidified to pH/Z with 3 N hydrochloric acid. 7-chloro 1,3 dihydro 3 hydroxy 5 phenyl 2H-1,4- benzodiazepin-Z-onecrystallized, melting point 197-200. More product could be obtained byacidification of the methanol filtrate obtained above.

EXAMPLE 15 To a solution of 2.0 g. (7 mmoles) of 8-chloro-1,3-dihydro-6-phenyl-2H-4,1,S-benzoxadiazocin 2 one in 25 ml. ofdimethylformamide, 0.5 g. (11 mmoles) of sodium hydride (60% in mineraloil) was added. After stirring for 15 minutes at room temperature, 1 ml.(2.27 g., 16 mmoles) of methyl iodide was added and the stirring wascontinued for 45 minutes. On addition of ice, a white solid separated.Filtration separated crude 8-chloro-1,3- dihydro 1 methyl 6phenyl-2H-4,1,5-benzoxadiazocin-2-one melting at 78-82 C.Recrystallization from hexane gave the pure product melting atl30.5-131.5.

EXAMPLE 16 A solution of 12.0 g. (52 mmoles) of2-amino-5-chlorobenzophenone and 11.7 g. (52 mmoles) ofcarbobenzoxyaminox-yacetic acid in 500 ml. of methylene chloride wascooled to in an ice bath and a solution of 11.6 g. (0.57 mmoles) ofdicyclohexylcarbodiimide in 125 ml. of methylene chloride was addeddropwise over a period of 1 hr. After 15 hrs. at room temperature, thereaction medium was filtered. Acetic acid (3 ml.) was added to thefiltrate, solvent was distilled off and the residue stirred withbenzene. The mixture was then again filtered. Solvent was distilled offfrom the last-mentioned filtrate under reduced pressure and the residue,dissolved in methylene chloride, was passed through a column ofFlorisil. Then, methylene chloride was passed through the column.Thereafter, elution with ethyl acetate separated a material.Crystallization of this material from a mixture of benzene and hexanegave 2-benzoyl 2 carbobenzoxyaminoxy-4'-chloroacetanilide, melting point113-114".

EXAMPLE 17 A solution of 7.25 g. of2'-benzoyl-2-carbobenzoxyaminoxy-4-chloroacetanilide in 75 ml. of 20%hydrobromic acid in acetic acid was stirred for 30 min. at roomtemperature. On addition of 750 ml. of anhydrous ether, a gummy solidformed. After decantation of the supernatant, the gummy residue waspartitioned between ether and sodium bicarbonate. The ether layer wasdried over sodium sulfate and concentrated to dryness. Crystallizationof the residue from a mixture of benzene and hexane gave 2aminoxy-2'-benzoyl-4'-chloroacetanilide (M.P. 85-86).

EXAMPLE 18 To a refluxing stirred solution of 12.5 g. of pyridinehydrochloride in 1250 ml. of pyridine, a solution of 12.5 g. of2-aminoxy-2'-benzoyl-4'-chloroacetanilide in 500 ml. of pyridine wasadded slowly during 90 min. Refluxing was continued for 5 hours, thenpyridine was removed by dis EXAMPLE 19 To a suspension of 100 g. (0.4mole) of 2-amino-5- chlorobenzophenone syn-oxime in 1500 ml. of ethanol,43.2 g. (0.8 mole) of sodium methoxide was added followed by 56 g. (0.4mole) of bromoacetic acid. The mixture was stirred and heated to refluxfor 2 hrs. Solvent was then removed by distillation under reducedpressure. The residue was partitioned between methylene chloride andwater. The organic layer 'was separated and the aqueous layer made morebasic by addition of 10% sodium hydroxide. The aqueous layer was againextracted with methylene chloride and filtered through I-Iy-Flo toremove a small amount of insoluble material. On standing, the sodiumsalt of N-(2-amino-5-chlorodiphenylmethylene)aminoxyacetic acid(syn-isomer) crystallized. It was separated by filtration, dissolved in2 l. of water and upon acidification with 3 N hydrochloric acid, thefree acid crystallized. After recrystallization from aqueous ethanol, N(2-amino-5-chl0rodiphenylmethylene)aminoxyacetic acid (syn-isomer)melting at 164-6 was obtained.

EXAMPLE 20 A solution of 25.0 g. (82 millimoles) of N-(2-amino-5-chlorodiphenylmethylene)aminoxyacetic acid syn-isomer in 1 l. oftetrahydrofuran was cooled to 5 and a solution of 15 g. (73 millimoles)of N,N'-dicyclohexylcarbodiimide in m1. of tetrahydrofuran was addedslowly. The mixture was stirred for 15 hrs. at room temperature andfiltered. To the filtrate, 2 ml. of acetic acid were added followed byabout 200 m1. of water. Distillation under reduced pressure removedtetrahydrofuran. The residue was dissolved in methylene chloride andwashed successively with water, 5% sodium bicarbonate, and saturatedsalt solution. After drying the organic layer over sodium sulfate, thesolvent was removed by distillation. The residue was dissolved in hotbenzene and filtered to remove a small amount of insoluble material. Onstanding, 8-chloro-1,3- dihydro-6-phenyl-2H-4,1,5-benzoxadiazocin-2-one,(M.P. 198-203") crystallized. From the mother liquor, after addition ofhexane, an impure fraction crystallized (M.P. 184-192).

EXAMPL'E 21 To a solution of 13.5 g. (0.1 mole) of o-aminoacetophenonein 200 ml. of ether, 100 ml. of water was added. While stirring, 20.2 g.(8.9 ml., 0.1 mole) of bromoacetyl bromide dissolved in 50 ml. of etherwas added slowly. At the same time, dilute sodium hydroxide was added tokeep the mixture slightly alkaline. The ether layer was separated,washed with water and dried over sodium sulfate. Solvent was thenremoved by distillation. The residue crys tallized from a mixture ofchloroform and hexane to give 2'-acetyl-2-bromoacetanilide melting at64-66.

EXAMPLE 22 A mixture of 25 g. (98 millimoles) of 2-acetyl-2-bromoacetanilide and 16 g. (98 millimoles) of N-hydroxyphthalimide in250 ml. of tetrahydrofuran containing 30 ml. of triethylamine wasstirred and heated at reflux for 1% hr. The solid that formed wasseparated by filtration and stirred with water. The water insolublematerial melted at 183-185 Recrystallization of the latter from amixture of chloroform and hexane gave pure 2'-acetyl-2-phthalimidoacetanilide melting at -186". On addition of waterto the tetrahydrofuran filtrate obtained above and removal oftetrahydrofuran by distillation under reduced pressure, an additionalamount of crude 2- acety1-2-phthalimidoacetanilide, M.P. 177-181 wasobtained. Recrystallization of the latter from a mixture of chloroformand hexane gave more of the pure product.

EXAMPLE 23 A solution of 25 g. (74 millimoles) of 2-acetyl-2-phthalimidoxyacetanilide in a mixture of 400 ml. of alcohol and 400 ml.of chloroform containing 8.5 g. of hydrazine hydrate and 8.5 ml. ofwater was kept at room temperature for 16 hrs. The solid that formed wasseparated by filtration. The filtrate was concentrated under 1 1 reducedpressure while adding water. The crystalline product,2-acetyl-2-aminoxyacetanilide, M.P. 103 106, was separated byfiltration. Recrystallization from a mixture of methylene chloride andhexane gave a pure product melting at 105-106.

EXAMPLE 24 A solution of 5 g. (24 millimoles) of2-acetyl-2-aminooxyacetanilide in 200 ml. of pyridine containing 5 g. ofpyridine hydrochloride was stirred and heated to reflux for 5 hrs.Pyridine was then removed by distillation under reduced pressure. Theresidue was partitioned between methylene chloride and water. Theorganic layer was washed successively with dilute hydrochloric acid,dilute sodium bicarbonate and water, then dried over sodium sulfate.After removal of the solvent by distillation, the residue was dissolvedin hot ethyl acetate and filtered. The filtrate was then concentrated toa small volume. Crystallization of1,3-dihydro-6-methyl-2H-4,1,S-benzoxadiazocin-Z-one, M.P. 2l4216occurred. After recrystallization of this product from benzene, it wasfound to melt at 2l6-217.

EXAMPLE 25 To a solution of 24.7 g. (0.1 mole) of2-amino-5-chlorobenzophenone syn-oxime in 500 ml. of ethanol and 36 ml.of 2.79 N sodium methoxide in methanol, 16.7 g. (0.1 mole) of ethylbromoacetate was added. The mixture was stirred and heated to reflux for2 hrs., then concentrated to a small volume under reduced pressure. Amethylene chloride solution of the residue was washed with water, driedover sodium sulfate and concentrated to dryness under reduced pressure.The residue was dissolved in benzene and passed through a column ofalumina. The benzene eluate was concentrated to dryness and crystallizedfrom cyclohexane to give crude N-(2- amino 5chlorodiphenylmethylene)aminoxyacetic acid ethyl ester, syn-isomermelting at 67-72. Recrystallization from hexane gave colorless needlesof pure product melting at 8284.

EXAMPLE 26 A solution of 5 g. (15 mmoles) ofN-(2-amino-5-chloro-diphenylmethylene) aminoxyacetic acid ethyl ester,syn-isomer and 2.9 g. (15 mmoles) of p-toluene sulfonic acid monohydratein 250 ml. of xylene was stirred and heated to reflux for 20 hrs. Xylenewas then removed by distillation under reduced pressure and the residuewas partitioned between methylene chloride and water. After drying oversodium sulfate, the organic layer was concentrated to dryness. Theresidue was triturated with warm benzene, filtered to remove insolublematerial and again concentrated to dryness. The residue was thentriturated with ethyl acetate to remove more insoluble material. Theresidue obtained after evaporation of ethyl acetate was dissolved inmethylene chloride and passed through a column of Florisil. Elution withether gave 8- chloro-1,3-dihydro-6-phenyl-2H-4,1,5-benzoxadiazocin 2-one which melted at 198-200 after recrystallization from benzene.

EXAMPLE 27 A solution of 28 mmoles of2'-benzoyl-2-bromo-4-chloro-propionanilide syn-oxime and 28 mmoles ofN-hydroyphthalimide and 8.6 ml. of triethylamine in 60 ml. oftetraliydrofuran was stirred and heated to reflux for 75 min. Aftercooling, filtration separated triethylamine hydrobromide. On addition ofhexane to the filtrate, crystallization occurred and the product wasseparated by filtration yielding 2-benzoyl 4'chloro-Z-(phthalimidooxy)-N-propionanilide, M.P. 164466.

EXAMPLE 28 A solution of 0.2 mole of 2-benzoyl-4-chloro-2-(phthalimidooxy)propionanilide in a mixture of 900 ml. of chloroform and900 ml. of ethanol containing 21 g. of hydrazine hydrate and 21 ml. ofwater was kept for 16 hrs. at room temperature. The gelatinousprecipitate of phthalhydrazide that formed was separated by filtration.The filtrate was concentrated under reduced pressure, after addition ofwater to remove chloroform and ethanol. The solid that separated wasremoved by filtration to yield2-aminoxy-2'-benzoyl-4'-chloropropionanilide. After recrystallizationfrom ethyl acetate, the product was found to have a melting point of104-106.

EXAMPLE 29 As in Example 9, 8-chloro-1,3-dihydro-3-methyl-6-phenyl 2H4,1,5 benzoxadiazocin-Z-one was prepared from2-aminoxy-2-benzoyl-4-chloropropionanilide. The so-prepared product hada melting point of 170172 after crystallization from methylene chlorideand hexane.

EXAMPLE 30 A parenteral formulation containing the followingingredients:

Per cc.

8-chloro-1,3-dihydro-6-phenyl-2H-4,1,5 benzoxadiazocin-Z-one mg 0.5Propylene glycol cc 0.4 Benzyl alcohol (benzaldehyde free) cc 0.015Ethanol USP cc 0.10 Sodium benzoate mg 48.8 Benzoic acid "mg-.." 1.2Water for injection q.s cc 1.0

were prepared (for 10,000 cc) as follows:

5 gm. of 8-chloro-1,3-dihydro-6-phenyl-2H-4,1,5-benzoxadiazocin-Z-onewere dissolved in cc. of benzyl alcohol; 4,000 cc. of propylene glycoland 1,000 cc. of ethanol were added. 12 gm. of benzoic acid weredissolved in the above. 488 gm. of sodium benzoate dissolved in 3,000cc. of Water for injection were added. The solution was brought up tofinal volume of 10,000 cc. with water for injection. The solution wasfiltered thru an 02 Selas candle, filled into suitable size ampuls,gassed with N and sealed. It was then autoclaved at 10 p.s.i. for 30minutes.

EXAMPLE 31 A capsule dosage formulation containing the followingingredients were prepared as follows:

Per capsule, mg. 8-chloro-1,3-dihydro-6-phenyl-2H-4,1,5benzoxadiazocin-Z-one 10 Lactose, U.S.P. Corn starch, U.S.P. 30 Talc,U.S.P. 5

Total weight 210 EXAMPLE 32 A tablet dosage formulation containing thefollowing ingredients:

Per tablet, mg. 8chloro-1,3-dihydro-6-phenyl-2H-4,1,5-benzoxadiazocin-Z-one 5.00Dicalcium phosphate dihydrate, unmilled 195.00 Corn starch 24.00Magnesium stearate 1.00

Total weight 225.00

were prepared as follows:

wherein A is selected from the group consisting of lower alkyl, C -Ccycloalkyl and R, R and R are selected from the group consisting ofhydrogen, halogen, nitro, trifluoromethyl and lower alkyl and R and Rare selected from the group consistingof hydrogen and lower alkyl.

2. A compound as defined in claim 1 wherein R and R are both hydrogenand A is the grouping 3}. A compound as defined in claim 2 wherein R ishalogen and R is hydrogen.

4. A compound as in claim 3 wherein R is hydrogen and R is chlorine,i.e., a compound of the formula 2-aminoxy-2'-benzoyl-4-chloroacetanilide.

5. A compound as defined in claim 2 wherein R is nitro.

6. A compound as defined in claim 5 wherein R and R are both hydrogen,i.e., a compound of the formula 2-aminoxy-Z-benzoyl-4'-nitroacetanilide.

I. A compound as defined in claim 2 wherein R and R are both hydrogenand R is trifluoromethyl, i.e., a compound of the formula2-aminoxy-2'-benzoyl-4'-trifluoromethylacetanilide.

8. A compound as defined in claim 2 wherein R R and R are all hydrogen,i.e., a compound of the formula 2-amihoxy-Z'-benzoylacetanilide.

9. A compound as in claim 1 wherein R, R R and R are all hydrogen and Ais lower alkyl, i.e., a compound of the formula 2-loweralkanoyl-2-aminoxyacetanilide.

10. A compound as defined in claim 1 wherein R, R R and R are allhydrogen and A is the lower alkyl group methyl; i.e., a compound of theformula 2'-acetyl-2-amin oxyacetanilide.

11. A compound as defined in claim 1 wherein A is the grouping R ishydrogen, R is halogen and R is methyl, i.e., a compound of the formula2-aminoxy-2-R -benzoylf-halopropionanilide.

References Cited UNITED STATES PATENTS 3,313,805 ,4/1967 Bell 260- 562HENRY R. J'ILES, Primary Examiner H. I. MOATZ, Assistant Examiner US.Cl. X.R.

260-239 ED, 326 N, 471 A, 519, 566 A; 424244

